title: DNA-damaging imidazoacridinone C-1311 induces autophagy followed by irreversible growth arrest and senescence in human lung cancer cells.
abstract: Imidazoacridinone 5-diethylaminoethylamino-8-hydroxyimidazoacridinone (C-1311) is an antitumor inhibitor of topoisomerase II and FMS-like tyrosine kinase 3 receptor. In this study, we describe the unique sequence of cellular responses to C-1311 in human non-small cell lung cancer (NSCLC) cell lines, A549 and H460. In A549 cells, C-1311 (IC80 = 0.08 µM) induced G1 and G2/M arrests, whereas H460 cells (IC80 = 0.051 µM) accumulated predominantly in the G1 phase. In both cell lines, cell cycle arrest was initiated by overexpression of p53 but was sustained for an extended time by elevated levels of p21. Despite prolonged drug exposure (up to 192 hours), no apoptotic response was detected in either cell line. Instead, cells developed a senescent phenotype and did not resume proliferation even after 2 weeks of post-treatment, indicating that C-1311-triggered senescence was permanent. When cell cycle arrest was evident but there were no signs of senescence, C-1311 significantly induced autophagic cells. Pharmacological inhibition of autophagy by 3-methyladenine profoundly reduced the senescent phenotype and slightly sensitized cancer cells to C-1311 by increasing cell death, suggesting a link between both autophagy and senescence. However, a small interfering RNA-mediated knockdown of the autophagy-associated Beclin 1 and ATG5 genes attenuated but failed to block development of senescence. Taken together, our studies suggest that in NSCLC, a C-1311-induced senescence program is preceded and corroborated but not exclusively determined by the induction of autophagy.
authors.affiliation: Department of Pharmaceutical Technology and Biochemistry, Gdańsk University of Technology, Gdańsk, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Polewska
authors.forename: Anna
authors.initials: A
authors.lastname: Skwarska
authors.forename: Ewa
authors.initials: E
authors.lastname: Augustin
authors.forename: Jerzy
authors.initials: J
authors.lastname: Konopa
mesh_terms: D000165:Acridine Orange; D000609:Aminoacridines / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D004249:DNA Damage / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D005456:Fluorescent Dyes; D016193:G1 Phase / Q000187:drug effects; D016195:G2 Phase / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology*; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D015388:Organelles / Q000187:drug effects; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D000609:Aminoacridines; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D005456:Fluorescent Dyes; D008565:Membrane Proteins; D001616:beta-Galactosidase; D000165:Acridine Orange; C098965:C 1311